Chronic pain is a major contributor to disability and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being preferred drugs.
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as xcexc, xcex4 and xcexa. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.
Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for xcexc, xcex4 and xcexa receptors had low affinity for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term xe2x80x9corphan receptorxe2x80x9d.
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.
The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor.
All documents cited herein, including the foregoing, are incorporated by reference in their entireties for all purposes.
It is accordingly an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.
It is an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor and one or more of the xcexc,xcex4 or xcexa receptors.
It is an object of certain embodiments of the present invention to provide new compounds for treating a patient suffering from chronic or acute pain by administering a compound having affinity for the ORL1 receptor.
It is an object of certain embodiments of the present invention to provide new compounds which have agonist activity at the xcexc, xcex4 and xcexa receptors which is greater than compounds currently available e.g. morphine.
It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering compounds which have agonist activity at the xcexc, d and k receptors which is greater than compounds currently available.
It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering non-opioid compounds which have agonist activity at the xcexc, xcex4 and xcexa receptors and which produce less side effects than compounds currently available.
It is an object of certain embodiments of the present invention to provide compounds useful as analgesics, anti-inflammatories, diuretics, anesthetics, neuroprotective agents, anti-hypertensives, anti-anxioltics; agents for appetite control; hearing regulators; anti-tussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, regulators of neurotransmitter and hormone release, kidney function modulators, anti-depressants, agents to treat memory loss due to Alzheimer""s disease or other dementias, anti-epileptics, anti-convulsants, agents to treat withdrawal from alcohol and drugs of addiction, agents to control water balance, agents to control sodium excretion and agents to control arterial blood pressure disorders and methods for administering said compounds.
The compounds of the present invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (ORL-1, xcexc, xcex4 and xcexa) centrally and/or peripherally. The response can be attributed to the compound stimulating (agonist) or inhibiting (antagonist) the one or more receptors. Certain compounds can stimulate one receptor (e.g., a xcexc agonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).
Other objects and advantages of the present invention will become apparent from the following detailed description thereof. The present invention in certain embodiments comprises compounds having the general formula (I): 
when the dotted line is a double bond, X1 and X2 are independently xe2x80x94CWxe2x80x94 wherein W is hydrogen, C1-10 alkyl C3-12 cycloalkyl, C3-12 cycloalkylC1-4alkyl-, C1-10 alkoxy, C3-12 cycloalkoxy-, C1-10 alkyl substituted with 1-3 halogen, C3-12 cycloalkyl substituted with 1-3 halogen, C3-12 cycloalkylC1-4alkyl- substituted with 1-3 halogen, C1-10 alkoxy substituted with 1-3 halogen, C3-12 cycloalkoxy- substituted with 1-3 halogen, xe2x80x94COOV1,xe2x80x94C1-4COOV1, xe2x80x94CH2OH, xe2x80x94SO2N(V1)2, hydroxyC1-10alkyl-, hydroxyC3-10cycloalkyl-, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, xe2x80x94CON(V1)2, NH2SO2C1-4alkyl-, NH2SOC1-4alkyl-, sulfonylaminoC1-10alkyl-, diaminoalkyl-, -sulfonylC1-4alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC1-4alkyl-, a 6-membered heteroaromaticC1-4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC1-4 alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC1-4alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC1-4alkyl-, xe2x80x94C1-5(xe2x95x90O)W1, xe2x80x94C1-5(xe2x95x90NH)W1, xe2x80x94C1-5NHC(xe2x95x90O)W1, xe2x80x94C1-5 NHS(xe2x95x90O)2W1, xe2x80x94C1-5NHS(xe2x95x90O)W1, wherein W1 is hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, xe2x80x94CH2OH, amino, C1-4alkylamino-, diC1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
wherein each V1 is independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, benzyl and phenyl;
when the dotted line is a single bond, X1 and X2 are independently selected from xe2x80x94CHOHxe2x80x94, xe2x80x94COxe2x80x94 and xe2x80x94CHW wherein W is as defined above;
Q, with the carbon atoms to which it is attached, is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
n is an integer from 0 to 3;
A, B and C are independently hydrogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, xe2x80x94CH2OH, xe2x80x94NHSO2, hydroxyC1-10alkyl-, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC1-10alkyl-, or A-B can together form a C2-6 bridge, or B-C can together form a C3-7 bridge, or A-C can together form a C1-5 bridge;
Z is selected from the group consisting of a bond, straight or branched C1-6 alkylene, xe2x80x94NHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2N(CH3)xe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94NHCH2COxe2x80x94, xe2x80x94CH2COxe2x80x94, xe2x80x94COCH2xe2x80x94, xe2x80x94CH2COCH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94Oxe2x80x94 and xe2x80x94HCxe2x95x90CHxe2x80x94, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino-, C3-12cycloalkylamino-, xe2x80x94COOV1, xe2x80x94C1-4COOV1, cyano, cyanoC1-10alkyl-, cyanoC3-10cycloalkyl-, NH2SO2xe2x80x94, NH2SO2C1-4alkyl-, NH2SOC1-4alkylxe2x80x94, aminocarbonyl-, C1-4alkylaminocarbonyl-, diC1-4alkylaminocarbonyl-, benzyl, C3-12 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (II): 
wherein X3 and X4 are independently selected from the group consisting of NH, O, S and CH2; and wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino-, C3-12cycloalkylamino-, or benzyl of R1 is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C1-10alkyl, C1-10alkoxy, nitro, trifluoromethyl-, cyano, xe2x80x94COOV1, xe2x80x94C1-4COOV1, cyanoC1-10alkyl-, xe2x80x94C1-5(xe2x95x90O)W1, xe2x80x94C1-5NHS(xe2x95x90O)2W1, xe2x80x94C1-5NHS(xe2x95x90O)W1, a 5-membered heteroaromaticC0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl-, C1-10 alkoxy-, and cyano; and wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (II) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl-and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group;
provided that ZR1 is not biphenyl-C1-2alkylene unsubstituted or substituted;
and pharmaceutically acceptable salts thereof and solvates thereof.
The present invention in certain embodiments comprises compounds having the formula (IA): 
when the dotted line is a double bond, X1 and X2 are both xe2x80x94CHxe2x80x94;
when the dotted line is a single bond, X1 and X2 are independently selected from xe2x80x94CH2xe2x80x94, xe2x80x94CHOHxe2x80x94, and xe2x80x94COxe2x80x94;
n is an integer from 0 to 3;
Z is selected from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CH2Oxe2x80x94; xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94CH2N(CH3)xe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94CH2CONHxe2x80x94, xe2x80x94NHCH2COxe2x80x94, xe2x80x94CH2COxe2x80x94, xe2x80x94COCH2xe2x80x94, xe2x80x94CH2COCH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CHxe2x95x90, and xe2x80x94HCxe2x95x90CHxe2x80x94, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with a lower alkyl, halogen, hydroxy or alkoxy group;
R1 is selected from the group consisting of hydrogen, C1-10alkyl, C3-12cycloalkyl, C2-10alkenyl, amino, C1-10alkylamino, C3-12cycloalkylamino, benzyl, C3-2 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (II): 
wherein X3 and X4 are independently selected from the group consisting of NH, O, S and CH2;
wherein said monocyclic aryl is preferably phenyl;
wherein said bicyclic aryl is preferably naphthyl;
wherein said alkyl, cycloalkyl, alkenyl, C1-10alkylamino, C3-12cycloalkylamino, or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, and spiro ring system of the formula (II) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10alkyl, C1-10alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkoxy, and cyano;
R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
provided that ZR1 is not biphenylmethyl;
and pharmaceutically acceptable salts thereof and solvates thereof.
In certain preferred embodiments of formula (I) or (IA), ZR1 is not biphenylC1-2alkylene unsubstituted or substituted. In other preferred embodiments, where the dotted line is a single bond, then Q is not phenyl, or is not a 6-membered ring. In other preferred embodiments Q is a 5-membered ring or a heteroaryl ring.
In certain preferred embodiments of formula (I), Q is phenyl or a 6 membered heteroaromatic group containing 1-3 nitrogen atoms.
In certain preferred embodiments of formula (I) or (IA), the R1 alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
In certain preferred embodiments of formula (I) or (IA), the R1 cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or norbornyl.
In other preferred embodiments of formula (I) or (IA), the R1 bicyclic ring system is naphthyl. In other preferred embodiments of formula (I) or (IA), the R1 bicyclic ring system is tetrahydronaphthyl, or decahydronaphthyl and the R1 tricyclic ring system is dibenzocycloheptyl.
In other preferred embodiments R1 is phenyl or benzyl.
In other preferred embodiments of formula (I) or (IA), the R1 bicyclic aromatic ring is a 10-membered ring, preferably quinoline or naphthyl.
In other preferred embodiments of formula (I) or (IA), the R1 bicyclic aromatic ring is a 9-membered ring, preferably indenyl.
In certain embodiments of formula (I) or (IA), Z is a bond, methyl, or ethyl.
In certain embodiments of formula (I) or (IA), the Z group is maximally substituted as not to have any hydrogen substitution on the base Z group. For example, if the base Z group is xe2x80x94CH2xe2x80x94, substitution with two methyl groups would remove hydrogens from the xe2x80x94CH2xe2x80x94 base Z group.
In other preferred embodiments of formula (I) or (IA), n is 0.
In certain embodiments of formula (I) or (IA), X3 and X4 are both 0.
In other preferred embodiments of formula (I) or (IA), the dotted line is a double bond. When the dotted line is a double bond, preferably one of X1 and X2 is CH and the other is not CH.
In embodiments of formula (I) or (IA) where the dotted line is a single bond, preferably one of X1 and X2 is CH2 and the other is not CH2.
In certain embodiments of formula (I), one of X1 and X2 is CH2 or CH and the other is CHW or CW wherein W is xe2x80x94CH2Cxe2x95x90ONH2; xe2x80x94C(NH)NH2, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, xe2x80x94Cxe2x95x90OCH3, xe2x80x94CH2CH2NHCxe2x95x90OCH3, xe2x80x94SO2CH3, CH2CH2NHSO2CH3, furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, or diazolemethyl-.
In certain embodiments of formula (I), ZR1 is cyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, or oxocanylpropyl-.
In certain embodiments of formula (I), at least one of ZR1 or W is xe2x80x94CH2COOV1, tetrazolylmethyl-, cyanomethyl-, NH2SO2methyl-, NH2SOmethyl-, aminocarbonylmethyl-, C1-4alkylaminocarbonylmethyl-, or diC1-4alkylaminocarbonylmethyl-.
In certain embodiments of formula (I), ZR1 is 3,3 diphenylpropyl optionally substituted at the 3 carbon of the propyl with xe2x80x94COOV1, tetrazolylC0-4alkyl-, cyano-, aminocarbonyl-, C1-4alkylaminocarbonyl-, or diC1-4alkylaminocarbonyl-.
In alternate embodiments wherein the dotted line is a double bond in formulae (I) or (IA), ZR1 can be the following 
wherein
Y1 is R3xe2x80x94(C1-C12)alkyl, R4-aryl, R5-heteroaryl, R6xe2x80x94(C3-C12)cyclo-alkyl, R7xe2x80x94(C3-C7)heterocycloalkyl, xe2x80x94CO2(C1-C6)alkyl, CN or xe2x80x94C(O)NR8R9; Y2 is hydrogen or Y1; Y3 is hydrogen or (C1-C6)alkyl; or Y1, Y2 and Y3, together with the carbon to which they are attached, form one of the following structures: 
wherein r is 0 to 3; w and u are each 0-3, provided that the sum of w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring E is a fused R4-phenyl or R5-heteroaryl ring;
R10 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, xe2x80x94OR8, xe2x80x94(C1-C6)alkyl xe2x80x94OR8, xe2x80x94NR8R9 and xe2x80x94(C1-C6)alkylxe2x80x94NR8R9;
R11 is 1 to 3 substituents independently selected from the group consisting of R10, xe2x80x94CF3, xe2x80x94OCF3, NO2 and halo, or R11 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C12)cycloalkyl, aryl and aryl(C1-C6)alkyl;
R3 is 1 to 3 substituents independently selected from the group consisting of H, R4-aryl, R6xe2x80x94(C3-C12)cycloalkyl, R5-heteroaryl, R7xe2x80x94(C3-C7)heterocycloalkyl, xe2x80x94NR8R9, xe2x80x94OR12 and xe2x80x94S(O)0-2R12;
R6 is 1 to 3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, R4-aryl, xe2x80x94NR8R9, xe2x80x94OR12 and xe2x80x94SR12;
R4 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR8, xe2x80x94(C1-C6)alkyl-OR8, xe2x80x94OCF3, xe2x80x94NR8R9, xe2x80x94(C1-C6)alkyl xe2x80x94NR8R9, xe2x80x94NHSO2R8, xe2x80x94SO2N(R14)2, xe2x80x94SO2R8, xe2x80x94NO2, xe2x80x94CONR8R9, xe2x80x94NR9COR8, xe2x80x94COR8, xe2x80x94COCF3, xe2x80x94OCOR8, xe2x80x94OCO2R8, xe2x80x94COOR8, xe2x80x94(C1-C6)alkyl-NHCOOC(CH3)3, xe2x80x94(C1-C6)alkyl-NHCOCF3, xe2x80x94(C1-C6)alkyl-NHSO2xe2x80x94(C1-C6)alkyl-NHCONHxe2x80x94(C1-C6)-alkyl and 
wherein f is 0 to 6; or R4 substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
R5 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, R13-aryl, (C3-C12)cycloalkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR8, xe2x80x94(C1-C6)alkyl-OR8, xe2x80x94OCF3xe2x80x94NR8R9, xe2x80x94(C1-C6)alkyl-NR8R9, xe2x80x94NHSO2R8, xe2x80x94SO2N(R14)2, xe2x80x94NO2, xe2x80x94CONR8R9, xe2x80x94NR9COR8, xe2x80x94COR8, xe2x80x94OCOR8, xe2x80x94OCO2R8 and xe2x80x94COOR8;
R7 is H, (C1-C6)alkyl, xe2x80x94OR8, xe2x80x94(C1-C6)alkyl-OR8, xe2x80x94NR8R9 or xe2x80x94(C1-C6)alkyl-NR8R9;
R12 is H, (C1-C6)alkyl, R4-aryl, xe2x80x94(C1-C6)alkyl-OR8, xe2x80x94(C1-C6)alkyl-NR8R9, xe2x80x94(C1-C6)alkyl-SR8, or aryl (C1-C6)alkyl;
R13 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
R14 is independently selected from the group consisting of H, (C1-C6)alkyl and R13xe2x80x94C6H4xe2x80x94CH2xe2x80x94;
provided that ZR1 is not biphenylmethyl or in certain preferred embodiments, ZR1 is not biphenylC1-2alkylene unsubstituted or substituted.
As used herein, the term xe2x80x9calkylxe2x80x9d means a linear or branched saturated aliphatic hydrocarbon group having a single radical and 1-10 carbon atoms. Examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branched alkyl means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or both hydrogens in a xe2x80x94CH2xe2x80x94 group of a linear alkyl chain. The term xe2x80x9clower alkylxe2x80x9d means an alkyl of 1-3 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d means an xe2x80x9calkylxe2x80x9d as defined above connected to an oxygen radical.
The term xe2x80x9ccycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyl and norbornyl.
The term xe2x80x9calkenylxe2x80x9d means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single radical and 2-10 carbon atoms. A xe2x80x9cbranchedxe2x80x9d alkenyl means that one or more alkyl groups such as methyl, ethyl or propyl replace one or both hydrogens in a xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90 linear alkenyl chain. Exemplary alkenyl groups include ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.
The term xe2x80x9ccycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond having a single radical and 3 to 12 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbornenyl. The term xe2x80x9carylxe2x80x9d means a carbocyclic aromatic ring system containing one, two or three rings which may be attached together in a pendent manner or fused, and containing a single radical. Exemplary aryl groups include phenyl, naphthyl and acenaphthyl.
The term xe2x80x9cheterocyclicxe2x80x9d means cyclic compounds having one or more heteroatoms (atoms other than carbon) in the ring, and having a single radical. The ring may be saturated, partially saturated or unsaturated, and the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; saturated 3- to 6-membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; saturated 3- to 6-membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, and dihydrofuran. Other heterocyclic groups can be 7 to 10 carbon rings substituted with heteroatoms such as oxocanyl and thiocanyl. When the heteroatom is sulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.
The term xe2x80x9cheteroarylxe2x80x9d means unsaturated heterocyclic radicals, wherein xe2x80x9cheterocyclicxe2x80x9d is as previously described. Exemplary heteroaryl groups include unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3 to 6-membered hetero-monocyclic groups containing an oxygen atom, such as furyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing a sulfur atom, such as thienyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term xe2x80x9cheteroarylxe2x80x9d also includes unsaturated heterocyclic radicals, wherein xe2x80x9cheterocyclicxe2x80x9d is as previously described, in which the heterocyclic group is fused with an aryl group, in which aryl is as previously described. Exemplary fused radicals include benzofuran, benzdioxole and benzothiophene.
As used herein, the term xe2x80x9cheterocyclicC1-4alkylxe2x80x9d, xe2x80x9cheteroaromaticC1-4alkylxe2x80x9d and the like refer to the ring structure bonded to a C1-4 alkyl radical.
All of the cyclic ring structures disclosed herein can be attached at any point where such connection is possible, as recognized by one skilled in the art.
As used herein, the term xe2x80x9cpatientxe2x80x9d includes a human or an animal such as a companion animal or livestock.
As used herein, the term xe2x80x9chalogenxe2x80x9d includes fluoride, bromide, chloride, iodide or alabamide.
The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.
The invention disclosed herein is also meant to encompass all prodrugs of the disclosed compounds. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo.
The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.
The invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
As used herein, the term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached.
The term xe2x80x9cenantiomerxe2x80x9d or xe2x80x9cenantiomericxe2x80x9d refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
The term xe2x80x9cracemicxe2x80x9d refers to a mixture of equal parts of enantiomers and which is optically inactive.
The term xe2x80x9cresolutionxe2x80x9d refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
The term xe2x80x9cmodulatexe2x80x9d as used herein with respect to the ORL-1 receptor means the mediation of a pharmacodynamic response (e.g., analgesia) in a subject from (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of the receptor activity. Compounds which modulate the receptor activity include agonists, antagonists, mixed agonists/antagonists and compounds which directly or indirectly affect regulation of the receptor activity.
Certain preferred compounds of the invention include:
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(p-benzyloxybenzyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(norbornan-2-yl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(decahydro-2-naphthyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undeca-9-yl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(1,3-dihydroinden-2-yl)-spiro[piperidine-4,1xe2x80x2-indene];
1-[4-(1-methylethyl)-cyclohexyl]-spiro[piperidine-4,1xe2x80x2-indene];
1-cyclodecyl-spiro[piperidine-4,1xe2x80x2-indene];
1-(naphth-1-yl-methyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(p-phenylbenzyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(4,4-Bis(p-fluorophenyl)butyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(3,3-Bis(phenyl)propyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(2-[1,2,3,4-tetrahydronaphthyl])-spiro[piperidine-4,1xe2x80x2-indene];
1-(4-[propylcyclohexyl])-spiro[piperidine-4,1xe2x80x2-indene];
1-(5-methylhex-2-yl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(cyclooctyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(cyclooctylmethyl)-spiro[piperidine-4,1xe2x80x2-indene];
1-(benzyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(naphth-1-yl-methyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(p-phenylbenzyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(4,4-Bis(p-fluorophenyl)butyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(3,3-Bis(phenyl)propyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(2-phenyl-ethyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(p-cyano-benzyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(p-benzyloxybenzyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(2-[1,2,3,4-tetrahydronaphthyl])-spiro[piperidine-4,1xe2x80x2-indane];
1-(4-propyl-cyclohexyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(5-methylhex-2-yl)-spiro[piperidine-4,1xe2x80x2-indane];
1-[norbornan-2-yl]-spiro[piperidine-4,1xe2x80x2-indane];
1-(decahydro-2-naphthyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(norbornan-7-yl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undeca-9-yl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(cyclooctyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(4-(1-methylethyl)-cyclohexyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(1,3-dihydroinden-2-yl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(cyclooctylmethyl)-spiro[piperidine-4,1xe2x80x2-indane];
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-cis-3a, 4, 5, 6, 7, 7a-hexahydroindane];
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-(2-oxo)-indane];
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-(1-hydroxy)-indane];
1-(naphth-2-yl-methyl)-spiro[piperidine-4,1xe2x80x2-(3-oxo)-indane]; and
pharmaceutically acceptable salts thereof and solvates thereof.
The present invention also provides use of any of the disclosed compounds in the preparation of a medicament for treating pain and other disease states modulated by an opioid receptor, e.g., the ORL-1 receptor.